Monoclonal antibody (mAb) 4C5 is a murine antibody that specifically recognizes both the a and to a lesser extent the β isoforms of the heat shock protein 90 (HSP90). Recently, HSP90 has become a very attractive drug-target for cancer therapy because most of its client proteins are considered to be key molecules in the acquisition of the malignant phenotype. Moreover, emerging data demonstrating the presence of this molecular chaperone at the surface of cancer cells suggest a wide-ranging phenomenon of extracellular chaperoning implicated in cancer cell invasion and metastasis.
MAb 4C5 was initially shown to inhibit cell migration processes in vitro during development of the nervous system by affecting actin cytoskeletal rearrangement and the formation of motile structures, such as lamellipodia. mAb 4C5 selectively binds to the surface pool of HSP90, and significantly reduces melanoma cell invasion and metastasis. Furthermore, mAb 4C5 was shown to inhibit the extracellular interaction between HSP90 and the growth factor receptor HER-2 in MDAMB453 breast cancer cells, leading to impaired downstream signalling and reduced cancer cell motility and invasion. Finally, mAb 4C5 was shown to inhibit a functional interaction between secreted HSP90 and pro-MMP2 and pro-MMP9, necessary for the activation of these enzymes which is essential for ECM degradation and cancer cell invasion and extravasation.
These combined data suggested that the capacity of mAb 4C5 to specifically inhibit the extracellular pool of HSP90 without affecting the wide range of important intracellular roles of this molecular chaperone could have clinical benefits in the treatment of human malignancies. However, murine mAbs do not constitute ideal therapeutic agents. An obvious problem with the use of murine mAbs in human clinical trials is the potential for the generation of human anti-mouse antibody responses. Initial attempts to use murine-derived mAbs in human therapeutics were hampered because murine antibodies were recognized by a human anti-murine-antibody immune response (HAMA) and the patient's immune system cut short the therapeutic window. These obstacles have been overcome by the advent of recombinant DNA technologies, which have led to the development of chimeric or humanized antibodies.